Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion.
Oxidative stress is thought to play an important role in the pathogenesis of Parkinson's disease (PD). Glutathione (GSH), a major cellular antioxidant, is decreased in the substantia nigra pars compacta of PD patients. The aim of the present study was to investigate whether deprenyl and its desmethyl metabolite, putative neuroprotective agents in the treatment of PD, could protect cultured rat mesencephalic neurons from cell death caused by GSH depletion due to treatment with L-buthionine-(S,R)-sulfoximine (BSO). BSO (10 microM) caused extensive cell death after 48 hr, as demonstrated by disruption of cellular integrity and release of lactate dehydrogenase into the culture medium. Both deprenyl and desmethylselegiline, at concentrations of 5 and 50 microM, significantly protected dopaminergic neurons from toxicity without preventing the BSO-induced loss in GSH. Protection was not associated with monoamine oxidase type B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and pretreatment with pargyline did not prevent the protective effects of deprenyl. Protection was not associated with inhibition of dopamine uptake by deprenyl because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. The antioxidant ascorbic acid (200 microM) also protected against BSO-induced cell death, suggesting that oxidative events were involved. This study demonstrates that deprenyl and its desmethyl metabolite can diminish cell death associated with GSH depletion.
Mytilineou
C
C
Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Leonardi
E K
EK
Radcliffe
P
P
Heinonen
E H
EH
Han
S K
SK
Werner
P
P
Cohen
G
G
Olanow
C W
CW
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000633:toxicity; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism*; D008454:Mazindol / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D012642:Selegiline / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000662:Amphetamines; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D012642:Selegiline; D019328:Buthionine Sulfoximine; C017861:desmethylselegiline; D010293:Pargyline; D008454:Mazindol; D014446:Tyrosine 3-Monooxygenase; D005978:Glutathione; D001205:Ascorbic Acid